Malaria parasites, which cause approximately one million deaths annually, undergo sexual differentiation and development in Anopheline mosquitoes. The sexual life cycle and transmission of Plasmodium parasites can be blocked when a refractory mosquito mounts an innate immune response against the parasites it carries. The objective of this proposal is to understand the genetic basis of refractory mechanisms in the mosquito. Anopheles gambiae is the principal vector for human malaria in Africa. A major type of immune response by this vector against Plasmodium parasites is the encapsulation of oocysts within melanin capsules on the mosquito midgut. The current knowledge of the genetic basis of this refractory response is very limited, except that three dominant quantitative trait loci (QTLs) have been identified against Plasmodium cynomolgi B. This proposal will take a combined approach of genetic mapping and QTL analyses to address three questions of broad interest. 1) How many QTLs in An gambiae are required for the encapsulation response? Specifically, the locus or loci for the encapsulation response against P. cynomolgi will be identified. 2) How do these QTLs interact and what is the sequence of molecular events during the response? The presence of a locus called Pif-B will be confirmed or disproved and its interactions with other encapsulation loci will be characterized using P. cynomolgi B as a target parasite. 3) Are the encapsulation loci identified with animal model parasites effective against P. falciparum, the most virulent human parasite. These questions will be answered through the genetic and QTL analyses of the encapsulation responses by different strains and colonies of mosquitoes against different Plasmodium parasites, including P. cynomolgi B and Ceylon and P. falciparum.